A Randomized Phase 3 Study of Tasisulam Administered as an Intravenous Infusion on Day 1 of a 28-Day Cycle vs. Paclitaxel as Second-Line Treatment in Patients with Metastatic Melanoma

Metastatic melanoma has remained a challenging clinical problem for over 3
decades,
with first-line treatment dacarbazine/temozolomide being little better than
best supportive
care. In addition, despite numerous clinical studies, no agent has been shown
to improve
the survival of patients failing front-line treatment. Although Study JZAF is
still in
progress, the response rate and number of tasisulam doses patients have
received are
encouraging, particularly since there were no limits imposed on the number of
prior
immuno-based treatments, pre-treatment LDH, or the presence or absence of
visceral
metastases. A recent meta-analysis of cooperative group trials in metastatic
melanoma
from 1975 to 2005 suggested that a 6-month PFS rate of 15% and a 1-year overall
survival rate of 25% were reasonable benchmarks for success for a Phase 2 study
(Korn
et al. 2008). The activity of tasisulam observed in second-line metastatic
melanoma
patients in Study JZAF provides rationale for further study for this novel
anti-cancer
agent in metastatic melanoma patients who have failed first-line dacarbazine or
temozolomide.

The primary objective of this study is to compare the overall survival (OS) of
patients who
have received one prior regimen of dacarbazine or temozolomide-based
chemotherapy for metastatic
melanoma when treated with either tasisulam or paclitaxel.

The secondary objectives of the study are the following:
To compare the following between treatment arms:
• time-to-event efficacy variables, including:
• progression-free survival (PFS)
• duration of response (DoR)
• deterioration in the FACT-M TOI score
• objective tumor response rate
• therapeutic benefit rate (TBR)
• measures of relative safety, including quantitative and qualitative
laboratory and non-laboratory toxicities
•health outcome measures, including the quality-adjusted life years (QALYs)
gained, time to worsening of health related quality of life (TWQ), and measures
of the patient*s well-being and symptoms.
Translational Research (TR):
• to evaluate the treatment-specific and treatment-independent effects of BRAF
and c-Kit mutational status on measures of clinical efficacy, including OS,
PFS, DoR, and response
• to evaluate the treatment-specific effects of genetic markers, including but
not limited to DMET genes such as CYP2C19 and CYP2C9, on measures of clinical
efficacy and toxicity.
• to assess other exploratory biomarkers relevant to tasisulam and paclitaxel
• to assess other exploratory biomarkers relevant to the disease state of
melanoma
• to assess the association between other exploratory biomarkers and clinical
outcome.

Study Design: This is a randomized, open-label, 2-arm, multicenter, Phase 3
investigation of tasisulam
versus paclitaxel after 1 previous systemic treatment with a dacarbazine or
temozolomide-based regimen for metastatic melanoma. Tasisulam will be
administered as a 2-hour intravenous (IV) infusion on Day 1 of a 28-day cycle.
Paclitaxel will be administered as a 1-hour IV infusion on Days 1, 8, & 15 of a
28-day cycle.
Approximately 800 patients are planned to be enrolled into the study world-wide
and the study will remain
open until approximately 600 events (deaths from any cause) have been observed.
Patients will be
randomized 1:1 to either tasisulam or paclitaxel treatment. Appropriate
efficacy measures will be recorded
every other cycle until progression, and upon discontinuation of treatment,
with the exception of physically
assessed lesion measurements which will be repeated every cycle before
tasisulam or paclitaxel
administration and at discontinuation of treatment as appropriate.

This is a randomized study with 2 arms to compare tasisulam versus paclitaxel
after 1 previous systemic treatment with a dacarbazine or temozolomide-based
regimen for metastatic melanoma.
Tasisulam will be administered as a 2-hour intravenous (IV) infusion on Day 1
of a 28-day cycle. Paclitaxel will be administered as a 1-hour IV infusion on
Days 1, 8, & 15 of a 28-day cycle

Side effects tasisulam / paclitaxel -> see question E9
Study procedures: blood, ECG, CT or MRI scans, see 'study schedule', protocol
pages 74 t/m 77 and question E6.